Glycine N-methyltransferase (GNMT), also known as a 4S polycyclic aromatic hydrocarbon (PAH) binding protein, has multiple functions. In addition to acting as a major folate binding protein (Yeo E J, et al. Proc Natl Acad Sci USA 1994; 91:210-214), it also regulates the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) by catalyzing sarcosine synthesized from glycine (Kerr S J. J Biol Chem 1972; 247:4248-4252). It was previously reported that the GNMT gene is down-regulated in HCC (Liu H H, et al. J Biomed Sci 2003;10:87-97). Results from a genetic epidemiological study indicate that GNMT is a tumor susceptibility gene for liver cancer (Tseng T L, et al. Cancer Res 2003; 63:647-654). In addition, it was reported that GNMT binds benzo(a)pyrene and prevents DNA-adduct formation (Chen S Y, et al. Cancer Res 2004;64:3617-3623).
In mice, GNMT expression is regulated by growth hormone, with the hepatocytes of female mice having up to eight times the expression level normally found in male mice. There have been three reports of pediatric patients (two boys, one girl) with congenital GNMT deficiencies resulting from a missense mutation in the GNMT gene (Augoustides-Savvopoulou P, et al. J Inherit Metab Dis 2003; 26:745-759). All three children had hypermethioninaemia, clinical symptoms mimicking chronic hepatitis (Augoustides-Savvopoulou P, et al. J Inherit Metab Dis 2003; 26:745-759). The girl had stunted growth and suffered from mental deficiency (IQ 87).
The prior art disclosed a GNMT knock-out mouse which showed abnormal liver function and suffered from glycogen storage disease (U.S. application Ser. No. 11/832,304).